Remimazolam: The Next Evolutionary Step for Sedative-Hypnotics.

Abstract

Lost in the avalanche of pandemic-related news last year was the commercial release of remimazolam (Byfavo, Acacia Pharma), formally announced on January 28, 2021. The journey of this highly anticipated novel benzodiazepine from discovery to market has been long and arduous. However, its arrival seems to herald a significant advancement for sedation and anesthesia for dentistry.The goal of identifying an ultrashort-acting benzodiazepine began in the late 1990s in the wake of remifentanil's discovery by the pharmaceutical company Glaxo Wellcome. Although several promising compounds were identified, Glaxo Wellcome opted to move forward with CNS 7259, formally named remimazolam in 2010.1 It changed hands several times throughout its development. where it was successfully paired with a besylate salt for clinical use. Remimazolam was ultimately acquired in 2008 by PAION AG, a German-based pharmaceutical company, which shepherded it through successful application to the US Food and Drug Administration (FDA) and subsequent phase I-III drug trials. In July 2020, remimazolam received US FDA approval for induction and maintenance of procedural sedation in adults. Similar approval was granted in Europe in 2021, as well as approval for general anesthesia in Japan and South Korea in 2020. An alternative (tosylate) salt form of remimazolam, likely developed by a Chinese company to circumvent patent issues, also received approval for procedural sedation in China.1 PAION AG partnered with Acacia Pharma to commercialize remimazolam in the US.The use of ultrashort-acting drugs is nothing new for most anesthesia providers given their familiarity with esmolol and remifentanil. Remimazolam combines virtually all the traditional benefits befitting a classic benzodiazepine, with an extremely rapid onset and favorable emergence profile facilitated by esterase-based metabolism. As a γ-aminobutyric acid type A (GABAa)-positive allosteric modulator, remimazolam is a potent sedative-hypnotic agent producing dose-dependent depression of the central nervous system (CNS), anxiolysis, anterograde amnesia, and anticonvulsant effects. It causes minimal cardiovascular and respiratory depression when judiciously administered alone, although the potential for synergistic and additive effects arises when it is given concurrently with other CNS depressants like opioids. Furthermore, as with any benzodiazepine, inadvertent overdose of remimazolam can be emergently reversed using flumazenil.What really separates remimazolam from rest of the benzodiazepine pack is its unique pharmacokinetic profile, specifically its esterase-based metabolism. It primarily undergoes rapid ester hydrolysis via carboxylesterase 1 (CES 1), a tissue esterase expressed in liver, lungs, and multiple other tissues, producing methanol and a relatively inactive carboxylic acid metabolite about 400 times weaker than its parent compound.1,2 Although some degree of hepatic microsomal enzymatic involvement has been noted, it appears to be virtually irrelevant with no evidence of cytochrome enzymatic induction or inhibition. The termination of remimazolam's clinical effects hinges on how quickly it is broken down and inactivated by CES 1 rather than its redistribution to inactive vessel-rich and vessel-poor tissue compartments like most short-acting agents (propofol, midazolam, fentanyl, etc). Although it can be administered as an intravenous (IV) bolus with repeated “top-ups” or mini-boluses, remimazolam has an ideal context-sensitive half-life (∼6-11 min) essentially mirroring that of remifentanil. Their shared pharmacokinetic similarities highlight the likely usefulness of remimazolam as a continuous infusion. As such, remimazolam has real potential to upend sedation and anesthesia for dentistry by supplanting the common sedative-hypnotics midazolam and propofol.Remimazolam is sold as a white lyophilized powder that requires reconstitution prior to use, yet another similarity it shares with remifentanil. Reconstitution with normal saline is recommended, and care must be taken as remimazolam is incompatible with lactated or acetated Ringer solutions, forming precipitate. Remimazolam is currently available for purchase in the US in a 20 mg/vial concentration at a cost of ∼$450.00 per box of 10 single-patient-use vials. As with most new drugs, the high initial cost is likely to ward off rapid expansion into the dental market. Presumably, the clear pharmacodynamic and pharmacokinetic benefits of remimazolam should prevail as financial considerations decrease.Assuming remimazolam's acceptance into dentistry as a procedural sedative and possibly as an off-label general anesthetic, it will be interesting to monitor how its use changes. During early phase I trials, healthy volunteers were given IV boluses over a 1-minute period of midazolam 0.075 mg/kg or remimazolam 0.075 to 0.2 mg/kg, and despite similar levels of sedation being observed, remimazolam had a significantly faster recovery time (10 vs 40 min) with virtually no significant differences in adverse events.3 In all 3 of the phase III studies (2 bronchoscopy and 1 colonoscopy), IV boluses of remimazolam (5 mg + 2.5-mg top-up) were again compared to midazolam (1.75 mg + 1-mg top-up) and placebo; however, it should be noted that fentanyl was coadministered for all subjects. Remimazolam had a significantly faster median procedure start time (5 vs 16 min) and time from procedure end to fully alert (6 vs 12 min). The average dose of remimazolam used in these studies ranged from 9 to 11.5 mg.1 Additionally, the safety profile of remimazolam was comparable to that of midazolam except for hypotension, which was noted less frequently with remimazolam in the colonoscopy study.4Although intermittent boluses were the predominant method of remimazolam administration during the early procedural sedation clinical trials, continuous infusions were used instead for trials evaluating it as a general anesthetic. Three studies used infusion rates of 6-12 mg/kg/h for induction and 1-2 mg/kg/h for maintenance; however, it must be noted that remifentanil and neuromuscular blockade (ie, rocuronium) were also used.1 Its use as an effective general anesthetic for dentistry in the office-based environment currently remains unclear.Remimazolam has clearly demonstrated strong potential as a sedative-hypnotic administered via intermittent bolus or continuous infusion. However, because it is a novel drug, data on remimazolam remain sparse. There have not yet been any published studies or case reports on its use for procedural sedation or general anesthesia for dentistry. Although its pharmacologic profile improves upon several of the noted drawbacks of midazolam (eg, liability for prolonged effects) and propofol (eg, liability for cardiorespiratory depression, injection pain), time will tell if these benefits are truly realized in the dental environment. I believe remimazolam's unique combination of pharmacologic features positions it nicely to be the leading IV sedative-hypnotic of dentistry, although its ascension and widespread use will take some time, primarily because of cost. Given its inherent reversibility, ease of titration, rapid onset and offset, clean metabolic profile, and low potential for significant cardiorespiratory depression as a solo agent, remimazolam has real potential to positively impact the landscape of anesthesia safety and efficiency in dentistry.